1. Field of the Invention
Modified metal oxides are provided. The modified metal oxides of this invention may be used as biomaterials that have surfaces that are resistant to cell adhesion. Processes to prepare the modified metal oxides of this invention are also disclosed.
2. Description of the Background Art
Inhibiting the non-specific adhesion of cells and proteins to biomaterials such as stents, catheters and guide wires is an important interfacial issue that needs to be addressed in order to reduce the surface related implant complications. Medical grade stainless steel 316L has been widely used as a biomaterial due to its corrosion resistance and very good mechanical properties. It is employed in many medical devices such as guide wires, orthopedic implants, and most commonly in the manufacture of vascular stents. Stents are used after angioplasty, a surgical method to clear the narrowing of the arteries, to prevent the re-closure of the artery. Though, this process is very successful, some complications arise due to thrombosis and neointima formation on the stents because like most artificial materials, stainless steel 316L provides a good surface for non-specific protein and cell adhesion. Therefore, interfacial modification to render the surface “inert” to attachment of proteins and cells is necessary. It is known that surface chemistry that prevents the protein and cell adhesion to the substrates, minimizes the host-implant (animal or human) inflammatory responses and prevents non-specific adhesion of proteins to render the substrate inert. However, research on surface modifications to stainless steel 316L used as a biomaterial is sparse. The present invention is a significant step towards mitigating cell adhesion by formation of monolayers with functionalized tail groups on 316L substrate.
In the past two decades, self assembled monolayers (SAMs) have developed as a commonly employed method to alter the interfacial properties of the material for their potential applications in the field of adhesion, corrosion inhibition, nano-lubricants and nano-scale devices. One of the most significant advantages of SAMs over other methods of surface coating is the ease in engineering interfacial structures at the molecular level and the ability to tailor the surface properties by functionalizing the terminal group of the SAMs. The model systems for SAMs have been thiols on gold and silanes on silicon.
Others have proposed oligoethylene glycol (OEG) terminated thiols on gold substrates as the model to render a surface inert to cellular and protein adhesion. There have been proposed that there are four characteristics of an inert surface: (1) the surface has to be polar, (2) has hydrogen bond acceptor groups, (3) no hydrogen bond donor groups, and (4) overall charge of the surface must be neutral. Inertness is a general property of a group of surfaces and not a specific property of OEG terminated SAMs, which are the model substrates for cell and protein resistance. According to this theory, hydrophobic surfaces are adsorbing. Others have proposed that more proteins adhere on hydrophobic surfaces due to hydrophobic effect by which proteins are expelled from the aqueous solution in order to increase hydrogen bonding among water molecules at the expense of less favorable water-protein interactions. Expelled proteins readily displace water from the hydrophobic surface region and get adsorbed.
Cooper et al. found that 3T3 fibroblasts and primary human osteoblasts attachment and spreading on methyl-terminated thiols on gold were poor compared to carboxylic acid terminated SAMs. Cooper et al. also found that the chain length affected the cell attachment only in case of methyl terminated thiols and not on hydroxyl and carboxylic acid terminated SAMs. Similar results were found using osteoblast cell lines where the focal contact and cell growth was highest for COOH terminated SAMs and least on methyl terminated thiols on gold. Using silane based self assembly, there have been several works on silicon which specify that hydrophobic substrates resist protein and cell adhesion more compared to controls and hydrophilic surfaces. It is believed that the cell adhesion on organically modified surfaces is a function of many parameters including but not limited to substrate, tail functionality, hydrophilicity and conformation of the monolayer on the substrate.
Although there is a large body of work performed on model substrates such as gold and silicon, these substrates cannot be employed in biomedical applications due to their poor mechanical properties and standard thiol chemistry has not been successfully employed on native SS316L and other oxides. Additionally, experiments, which utilized gold coated and uncoated stainless steel stents in patients with coronary artery disease, showed an increased risk of restenosis after placement of gold-coated stents in patients vs. uncoated stents. It is noteworthy that though stainless steel 316L is widely used as a biomaterial, the surface has been pretreated to remove the oxide layer.
Shustak et al. (Langmuir 2004, 20(18): pages 7499-7506) observed bidentate bonding on the electrochemically induced dodecanoic acid SAMs adsorbed on 316L stainless steel substrates, which were modified by fast electrochemical deposition of the acid by applied electrical potential.
In spite of this background art, there remains a very real and substantial need for a modified metal oxide, and more specifically a modified metal oxide that may be used as a biomaterial that is resistant to surface cell adhesion, and a process for making the modified metal oxide.